Organic compounds will continue to dominate molecular medicine as drug agents for the foreseeable future, and with few exceptions, these substances must be chemically synthesized. Synthesis enables the evaluation of bioactive organic molecules at all levels: cellular target identification, elucidation of biological mechanism, drug target validation, lead identification, and optimization and production of clinical candidates. The limitations of chemical synthesis often present a substantial obstacle to the study of bioactive molecules. Improved understanding of reactivity, development of effective and concise methods, and refinement of synthetic strategies are required to accelerate the process of understanding disease and advancing molecular medicine. This research will develop innovative methods to relieve these bottlenecks based on spirodiepoxides (SDEs), the double epoxidation products of allenes. Combined with flexible and convergent methods of allene synthesis, SDE-based transformations will enable direct entry into a wide range of molecular motifs that abound in natural products and complex pharmaceutical. The long-term goals of this research are to establish a in-depth understanding of SDE reactivity, to develop methods based on SDEs, and to refine synthetic strategies in the application of these methods to the synthesis of chemically and medicinally relevant targets. The specific aims of this proposal are to develop methods for carbon nucleophile opening of SDEs and apply to the synthesis of 9-(S)-dihydroerythronolide A, a precursor to an important class of antibiotics. Second, to refine methods for stereoselective SDE formation and intramolecular heteroatom nucleophile SDE-openings focused on the synthesis of pyrans and furans and will be utilized in the synthesis of psymberin and pectenotoxin 4, which are antitumor agents. Lastly, we will develop methods for the synthesis of highly oxygenated motifs including vicinal polyols.